When nutrients are taken orally, there is greater insulin secretion than when the same amount of these nutrients are given intravenously. The factor(s) in the gastrointestinal (GI) tract which are responsible for enhancement of insulin secretion ("incretin(s)") have not been fully characterized. We have developed an isolated, perfused rat intestine preparation to apply to the search for such factor(s). Feeding this preparation a glucose solution or an electrolyte solution results in an enteric portal venous effluent (EPVE) which will enhance insulin secretion from the isolated, perfused pancreas of another rat. This enhancing factor is absent in EPVE of unfed gut or EPVE from fed gut of old rats. Known GI hormones have different effects on rat pancreas secretion when compared with EPVE. OBJECTIVES: 1. Physiologic: (a) To continue studies of comparative biologic effects of known major and new GI hormones with those of EPVE. (b) To test effects of feeding a variety of nutrients upon the properties of EPVE. (c) To find out which segment of bowel are richest in factors which enhance insulin secretion. (d) To study physiologic conditions requisite for optimal "incretin" secretion. 2. Immuno-chemical: Application of currently available immunoassays for GI hormones to analysis of EPVE. 3. Chemical: Protein isolation and purification methods and other assays will be applied to EPVE to determine if it contains new factors or hormones acting as "incretin(s)". 4. Pathophysiologic: To continue studies in rats and in man, assessing enteric factors that modify insulin secretion in health and in diabetes. Ultimate objectives of this work are to test the hypotheses: "Incretin(s) can be characterized physiologically and chemically, in EPVE. The gut-islet axis may be a pathophysiologically significant defect in diabetes, especially the non-obese, adult onset variety."